The use of tracer compounds, which emit radiation from within the body, as medical tools has long been known. Such materials have been used for testing liver function and biliary patency, for the analysis of the physiological structure and function of the kidneys, for imaging bone marrow, for scanning the skeletal bone structure of mammals, for blood pool imaging, for detecting tumors, and for analysis of the lungs, etc.
Another development in radionuclide use is the detection, location and assessment of infarcts in various areas of the body. An infarct is a region of dead tissue caused by complete interference with the blood supply to that tissue usually as the result of occlusion of the supplying artery. Infarcts can occur in essentially any area of the body, the most serious including infarcts in the brain and infarcts in myocardium or heart muscle, caused by thrombi, embolisms, arterial sclerosis, etc. A number of attempts have been made to use radionuclides to confirm the presence of infarcts, and to give an assessment of their size and situs.
Radioactively-labelled compounds which are selectively incorporated into infarcted tissue have been used for such purposes. Such agents include radioactive mercury derivatives of chlormerodrin and fluorescein, and technetium-labelled tetracycline, pyrophosphate and diphosphonates. See, Hubner, Cardiovascular Research 4:509 (1970) and Holman et al., J. of Nuclear Medicine 14:95 (1973).
Technetium-99m (.sup.99m Tc) is a preferred radionuclide for radioactively scanning organs because of its short half-life and because it radiates gamma rays which can be easily measured, compared, for example, to beta rays. See Radiology, Vol. 99, April 1971, pages 192-196.
The use of technetium-99m in radiopharmaceutical form has become an important non-invasive method for diagnosis with wide ranging medical application because of its ready availability from a generator source, 140 KeV gamma radiation, and 6-hour half-life.
Technetium-99m is obtained from either extraction from Molybdenum-99 with a solvent such as methyl ethyl ketone or elution from a column of alumina or other support on which is adsorbed the parent isotope Molybdenum-99 with an aqueous media. The most stable chemical form assumed under these conditions is pertechnetate (TcO.sub.4.sup.-) in a + 7 oxidation state. Most technetium-based radiopharmaceuticals, however, require a reduction to the +3, +4 or +5 oxidation state. Presently, these radiopharmaceuticals are frequently produced by combining an excess of the compound needed for labeling with a reducing agent, freeze-drying this mixture and adding pertechnetate.
Suitable reducing agents have been known for some time. Examples of such include divalent stannous ion (Sn.sup.++) in the form of stannous chloride, tartrate, and phosphate, ferrous compounds (Fe.sup.++), ferric-ascorbate complexes and reduced zirconium. Such reducing agents are used to bind radioactive .sup.99m Tc to carriers, such as chelating agents, red blood cells, albumin and other proteins, and various other compounds which selectively seek out certain organs of the body, in order to carry the .sup.99m Tc with them to such organs of the body where it is concentrated, whereby such organ can be radioactively scanned or imaged for diagnostic or other purposes, e.g. radioactive treatment of a pathological condition. See Journal of Nuclear Medicine, Vol. 11, No. 12, 1970, page 761; Journal of Nuclear Medicine, Vol. 12, No. 1, 1971, pages 22-24; Journal of Nuclear Medicine, Vol. 13, No. 2, 1972, pages 180-181; Journal of Nuclear Medicine, Vol. 12, No. 5, May 1971, pages 204-211; Radiology, Vol. 102 , January 1972, pages 185-196; Journal of Nuclear Medicine, Vol. 13, No. 1, 1972, pages 58-65.
Generally a radiopharmaceutical product containing a technetium-99mm labelled ligand (.sup.99m Tc-L) is made by mixing two components. A first component containing a reducing agent, such as stannous ions, and the ligand (L) to be labelled is mixed with radioactive pertechnetate solution from a generator to obtain the product. Thus, the radiopharmaceutical product contains technetium labelled ligand, stannous and stannic-ligand complexes, and excess ligand which is used to make sure that stannous or stannic salts do not precipitate out of solution and to reduce the quantity of free pertechnetate or reduced uncomplexed technetium in the solution, i.e. technetium that is not bound or complexed with the ligand.
Certain disadvantages can be found in the above procedure. First, although the reducing agent is not necessary for the functioning of the resulting radiopharmaceutical product, it remains in the product and is injected into the patient. While the presence of tin or other reducing agents generally used to make these products has not been found harmful, it is not desirable to inject unnecessary chemicals into a patient. Thus, it would be desirable to separate or eliminate the reducing agent from the final product.
Another disadvantage occurs when the ligand to be labelled is rare or difficult to obtain, or where the ligand to be labelled could be harmful to the patient and the amount injected must be minimized. Under such circumstances it is desirable to efficiently label small quantities of the ligand and not use any excess ligand in the labelling process.
U.S. Pat. Nos. 4,001,387; 3,902,849 and 3,749,556 describe radiopharmaceutical generator kits in which particulate or sintered reducing agent is used to reduce the technetium-99m. As described therein, the reducing agent absorbs the technetium-99m and then reduced technetium-99m is eluted using a solution of the ligand to be labelled. The eluate thus contains technetium-99m labelled ligand. The eluant may be passed through a strongly acidic ion exchange column to eliminate any uncombined reducing agent. Thus, apparently reducing agent-ligand complexes formed during reduction and elution remain in the product.
When stannous chloride is used conventionally as a reducing agent for labelling .sup.99m Tc radiopharmaceuticals, the excess tin is also chelated by the compound being tagged. Excess uncomplexed tin often forms a colloid which interferes with the use of the product. For most .sup.99m Tc labelled radiopharmaceuticals, tin is not an integral part of the Tc-complex but serves only as a reducing agent for pertechnetate. Therefore, it can be easily appreciated that a reduction/labeling system in which reducing agent is eliminated in the final labelled product would be highly desirable.